Background: Diabetes mellitus is a chronic and overwhelming disease that is managed by insulin. Subcutaneous insulin injection has several disadvantages such as nerve damage, microbial contamina-tion, thermolabile, and pain. Exogenous insulin is essential for the management of Diabetes mellitus type 1 and has an adjunct role in the management of type 2 diabetes mellitus in which oral hypoglycemic medicines display the leading management role. Pain, Lipodystrophy at the injection site, Nerve damage, Thermolabile and microbial contamination during injection are the principal adverse effects of insulin administered via IV or SC routes. The aim of the study: Development of different oral drug delivery systems by bio-informatics and |peptidomimetics. Methodology: In this study, insulin was prepared by recombinant DNA technology using bioinformatics technology via the addition of cysteine-cysteine beside each other in the alpha-helices of the core of the two subunits of insulin. Protease inhibitor and polymeric adhesive were added with oral film enteric-coated insulin tablets of insulin. The test insulin was tested on animal models and compared with standard subcutaneous insulin for efficacy. The human insulin tablets were prepared by wet granulation technique utilizing different concentrations of starch, sucrose, talc and sodium caroxy methylcellulose. DSC and FTIR spectroscopy were utilized in the drug and the polymer compatibility studies. Evaluation of preformulation properties of active principal ingredient(API) was performed. As well postcompressional parameters as wetting time, disintegration time, in vivo bio-availability, in vitro drug release, water absorption ratio study of the optimized formulation were assessed. Results: In this research, we designed and developed thermostable and acid-stable insulin that can be formulated as an oral drug delivery system and can be taken also by the sublingual route. The efficacy of the test insulin was nearly 60% during human clinical trials phases 1/2. Conclusion: The new thermostable and acid-stable insulin helped to overcome the disadvantages of subcutaneous injections of insulin.